Abstract
Activation of Wnt/β-catenin signaling is essential for colorectal carcinogenesis. Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, is a positive regulator of the Wnt/β-catenin signaling. Accordingly, tankyrase inhibitors are under preclinical development for colorectal cancer (CRC) therapy. However, Wnt-driven colorectal cancer cells are not equally sensitive to tankyrase inhibitors, and cellular factors that affect tankyrase inhibitor sensitivity remain elusive. Here, we established a tankyrase inhibitor-resistant cell line, 320-IWR, from Wnt/β-catenin-dependent CRC COLO-320DM cells. 320-IWR cells exhibited resistance to tankyrase inhibitors, IWR-1 and G007-LK, but remained sensitive to a PARP-1/2 inhibitor, olaparib, and several anti-CRC agents. In 320-IWR cells, nuclear localization of active β-catenin was decreased and expression of β-catenin target genes was constitutively repressed, suggesting that these cells repressed the Wnt/β-catenin signaling and were dependent on alternative proliferation pathways. 320-IWR cells exhibited upregulated mTOR signaling and were more sensitive to mTOR inhibition than the parental cells. Importantly, mTOR inhibition reversed resistance to tankyrase inhibitors and potentiated their anti-proliferative effects in 320-IWR cells as well as in CRC cell lines in which the mTOR pathway was intrinsically activated. These results indicate that mTOR signaling confers resistance to tankyrase inhibitors in CRC cells and suggest that the combination of tankyrase and mTOR inhibitors would be a useful therapeutic approach for a subset of CRCs.
Highlights
Colorectal cancer (CRC) is a leading cause of cancer death worldwide
Growth inhibition by IWR-1 and another tankyrase inhibitor G007-LK was strongly prevented in these β-catenin mutant-expressing cells (Figure 1B). These results indicate that down-regulation of active β-catenin is a critical step in the growth inhibition of COLO-320DM cells treated with tankyrase inhibitors
We established a tankyrase inhibitorresistant cell line, 320-IWR. 320-IWR cells were resistant to multiple tankyrase inhibitors with different structures, whereas they did not show cross-resistance to a PARP1/2 inhibitor
Summary
Colorectal cancer (CRC) is a leading cause of cancer death worldwide. In the treatment of metastatic CRC, conventional chemotherapy and several molecularlytargeted drugs are currently used as standard drugs [1]. Together with mutations in oncogenes and tumor suppressor genes, such as KRAS, p53, and SMAD4, activation of the canonical Wnt/β-catenin signaling pathway is a critical event in colorectal tumorigenesis. The Wnt/β-catenin signaling activation is mainly caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene [3]. In most sporadic CRC cases, mutations in APC occur, which lead to stabilization of β-catenin and activation of www.impactjournals.com/oncotarget downstream TCF/LEF-mediated transcription [3, 4]. The Wnt/β-catenin pathway plays an essential role in CRC initiation and in tumor maintenance [5]. These observations indicate that Wnt/β-catenin signaling is a rational therapeutic target for CRC
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